Dexamethasone potentiates chimeric antigen receptor T cell persistence and function by enhancing IL-7Rα expression.

Dexamethasone (dex) is a glucocorticoid that is a mainstay for the treatment of inflammatory pathologies, including immunotherapy-associated toxicities, yet the specific impact of dex on the activity of CAR T cells is not fully understood. We assessed whether dex treatment given ex vivo or as an adjuvant in vivo with CAR T cells impacted the phenotype or function of CAR T cells. We demonstrated that CAR T cell expansion and function were not inhibited by dex. We confirmed this observation using multiple CAR constructs and tumor models, suggesting that this is a general phenomenon. Moreover, we determined that dex upregulated interleukin-7 receptor α on CAR T cells and increased the expression of genes involved in activation, migration, and persistence when supplemented ex vivo. Direct delivery of dex and IL-7 into tumor-bearing mice resulted in increased persistence of adoptively transferred CAR T cells and complete tumor regression. Overall, our studies provide insight into the use of dex to enhance CAR T cell therapy and represent potential novel strategies for augmenting CAR T cell function during production as well as following infusion into patients.

A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.

Facet-Engineered BiVO4 Photocatalysts for Water Oxidation: Lifetime Gain Versus Energetic Loss.

A limiting factor to the efficiency of water Oxygen Evolution Reaction (OER) in metal oxide nanoparticle photocatalysts is the rapid recombination of holes and electrons. Facet-engineering can effectively improve charge separation and, consequently, OER efficiency. However, the kinetics behind this improvement remain poorly understood. This study utilizes photoinduced absorption spectroscopy to investigate the charge yield and kinetics in facet-engineered BiVO4 (F-BiVO4) compared to a non-faceted sample (NF-BiVO4) under operando conditions. A significant influence of preillumination on hole accumulation is observed, linked to the saturation and, thus, passivation of deep and inactive hole traps on the BiVO4 surface. In DI-water, F-BiVO4 shows a 10-fold increase in charge accumulation (∼5 mΔOD) compared to NF-BiVO4 (∼0.5 mΔOD), indicating improved charge separation and stabilization. With the addition of Fe(NO3)3, an efficient electron acceptor, F-BiVO4 demonstrates a 30-fold increase in the accumulation of long-lived holes (∼45 mΔOD), compared to NF-BiVO4 (∼1.5 mΔOD) and an increased half-time, from 2 to 10 s. Based on a simple kinetic model, this increase in hole accumulation suggests that facet-engineering causes at least a 50-100 meV increase in band bending in BiVO4 particles, thereby stabilizing surface holes. This energetic stabilization/loss results in a retardation of OER relative to NF-BiVO4. This slower catalysis is, however, offset by the observed increase in density and lifetime of photoaccumulated holes. Overall, this work quantifies how surface faceting can impact the kinetics of long-lived charge accumulation on metal oxide photocatalysts, highlighting the trade-off between lifetime gain and energetic loss critical to optimizing photocatalytic efficiency.

Degradation Evolution for Li2 ZrCl6 Electrolytes in Humid Air and Enhanced Air Stability via Effective Indium Substitution.

Superionic halides have aroused interests in field of solid electrolytes such as Li2 ZrCl6 . However, they are still facing challenges including poor air stability which lacks in-depth investigation. Here, moisture instability of Li2 ZrCl6 is demonstrated and decomposition mechanism in air is clearly revealed. Li2 ZrCl6 decomposes into Li2 ZrO3 , ZrOCl2 ·xH2 O and LiCl during initial stage as halides upon moisture exposure. Later, these side products evolve into LiCl(H2 O) and Li6 Zr2 O7 after longer time exposure. More importantly, structure of destroyed halides cannot be recovered after postheating. Later, Indium is doped into Li2 ZrCl6 (9.7 × 10-5 S cm-1 ) to explore its effect on structure and properties. Crystal structure of ball-milled In-doped Li2 ZrCl6 electrolytes is converted from the Li3 YCl6 -like to Li3 InCl6 -like with increasing In content and ionic conductivity can also be enhanced (0.768-1.13) × 10-3 S cm-1 ). More importantly, good air stability of optimal Li2.8 Zr0.2 In0.8 Cl6 is achieved since halide hydrates are formed after air exposure instead of total decomposition and the hydrates can be restored to Li2.8 Zr0.2 In0.8 Cl6 after postheating. Moreover, reheated Li2.8 Zr0.2 In0.8 Cl6 after air exposure is successfully applied in solid-state LiNi0.8 Co0.1 Mn0.1 O2 /halides/Li6 PS5 Cl/Li-In battery. The results in this work can provide insights into air instability of Li2 ZrCl6 and effective strategy to regulate air stability of halides.

Nano-Interfacial Supramolecular Adhesion of Metal-Organic Framework-Based Separator Enables High-Safety and Wide-Temperature-Range Lithium Batteries.

Polyolefin separators are the most commonly used separators for lithium batteries; however, they tend to shrink when heated, and their Li+ transference number (t Li +) is low. Metal-organic frameworks (MOFs) are expected to solve the above problems due to their high thermal stability, abundant pore structure, and open metal sites. However, it is difficult to prepare high-porosity MOF-based membranes by conventional membrane preparation methods. In this study, a high-porosity free-standing MOF-based safety separator, denoted the BCM separator, is prepared through a nano-interfacial supramolecular adhesion strategy. The BCM separator has a large specific surface area (450.22 m2 g-1) and porosity (62.0%), a high electrolyte uptake (475 wt%), and can maintain its morphology at 200 °C. The ionic conductivity and t Li + of the BCM separator are 1.97 and 0.72 mS cm-1, respectively. Li//LiFePO4 cells with BCM separators have a capacity retention rate of 95.07% after 1100 cycles at 5  C, a stable high-temperature cycling performance of 300 cycles at 80 °C, and good capacity retention at -40 °C. Li//NCM811 cells with BCM separators exhibit significantly improved rate performance and cycling performance. Pouch cells with BCM separators can work at 120 °C and have good safety at high temperature.

Nuclear receptors for epidermal lipid barrier: Advances in mechanisms and applications.

The skin plays an essential role in preventing the entry of external environmental threats and the loss of internal substances, depending on the epidermal permeability barrier. Nuclear receptors (NRs), present in various tissues and organs including full-thickness skin, have been demonstrated to exert significant effects on the epidermal lipid barrier. Formation of the lipid lamellar membrane and the normal proliferation and differentiation of keratinocytes (KCs) are crucial for the development of the epidermal permeability barrier and is regulated by specific NRs such as PPAR, LXR, VDR, RAR/RXR, AHR, PXR and FXR. These receptors play a key role in regulating KC differentiation and the entire process of epidermal lipid synthesis, processing and secretion. Lipids derived from sebaceous glands are influenced by NRs as well and participate in regulation of the epidermal lipid barrier. Furthermore, intricate interplay exists between these receptors. Disturbance of barrier function leads to a range of diseases, including psoriasis, atopic dermatitis and acne. Targeting these NRs with agonists or antagonists modulate pathways involved in lipid synthesis and cell differentiation, suggesting potential therapeutic approaches for dermatosis associated with barrier damage. This review focuses on the regulatory role of NRs in the maintenance and processing of the epidermal lipid barrier through their effects on skin lipid synthesis and KC differentiation, providing novel insights for drug targets to facilitate precision medicine strategies.

Is low-dose computed tomography for lung cancer screening conveniently accessible in China? A spatial analysis based on cross-sectional survey.

BACKGROUND: Regular Low-Dose Computed Tomography (LDCT) for lung cancer high-risk population has been proved to improve health outcomes and relieve disease burden efficiently for both individual and society. With geographical impedance becoming the major barrier preventing patients from getting timely healthcare service, this study incorporated health seeking behavior in estimating spatial accessibility of relative scarce LDCT resource in China, thus to provide real-world evidence for future government investment and policy making. METHODS: Taking Sichuan Province in southwest China as the study area, a cross-sectional survey was first carried out to collect actual practice and preferences for seeking LDCT services. Using Computed Tomography (CT) registration data reported by owner institutions representing LDCT services capacity, and grided town-level high-risk population as demand, the Nearest Neighbor Method was then utilized to calculate spatial accessibility of LDCT services. RESULTS: A total of 2,529 valid questionnaires were collected, with only 34.72% of the high-risk populations (746 individuals) followed the recommended annual screening. Participants preferred to travel to municipal-level and above institutions within 60 min for LDCT services. Currently, every thousand high-risk populations own 0.0845 CT scanners in Sichuan Province, with 96.95% able to access LDCT within 60 min and over half within 15 min. Urban areas generally showed better accessibility than rural areas, and the more developed eastern regions were better than the western regions with ethnic minority clusters. CONCLUSIONS: Spatial access to LDCT services is generally convenient in Sichuan Province, but disparity exists between different regions and population groups. Improving LDCT capacity in county-level hospitals as well as promoting health education and policy guidance to the public can optimize efficiency of existing CT resources. Implementing mobile CT services and improving rural public transportation may alleviate emerging disparities in accessing early lung cancer detection.

Abnormal intrinsic brain functional network dynamics in first-episode drug-naïve adolescent major depressive disorder.

BACKGROUND: Alterations in brain functional connectivity (FC) have been frequently reported in adolescent major depressive disorder (MDD). However, there are few studies of dynamic FC analysis, which can provide information about fluctuations in neural activity related to cognition and behavior. The goal of the present study was therefore to investigate the dynamic aspects of FC in adolescent MDD patients. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 94 adolescents with MDD and 78 healthy controls. Independent component analysis, a sliding-window approach, and graph-theory methods were used to investigate the potential differences in dynamic FC properties between the adolescent MDD patients and controls. RESULTS: Three main FC states were identified, State 1 which was predominant, and State 2 and State 3 which occurred less frequently. Adolescent MDD patients spent significantly more time in the weakly-connected and relatively highly-modularized State 1, spent significantly less time in the strongly-connected and low-modularized State 2, and had significantly higher variability of both global and local efficiency, compared to the controls. Classification of patients with adolescent MDD was most readily performed based on State 1 which exhibited disrupted intra- and inter-network FC involving multiple functional networks. CONCLUSIONS: Our study suggests local segregation and global integration impairments and segregation-integration imbalance of functional networks in adolescent MDD patients from the perspectives of dynamic FC. These findings may provide new insights into the neurobiology of adolescent MDD.

Effect of Shock-Wave-Mediated Collapse on Nanobubble Characteristics.

To enhance the comprehension of the cavitation mechanism and explore its practical use in industrial production, this study developed models involving oxygen, varying bubble radii, and bubble quantities. This study uses molecular dynamics simulations coupled with the momentum mirror method to examine the collapse characteristics of bubbles during ultrasonic cavitation. The investigation uncovers patterns in the fluctuation of the maximum local density of water molecules, released pressure, and temperature. The findings demonstrate that, when oxygen-containing bubbles collapse at identical radii, the local density is notably higher and diminishes more rapidly. Moreover, the changes in the shape exhibit greater regularity. During the bubble collapse, a depression forms on the bubble's surface, coinciding with a notable surge in local density around the depression. As bubble radii and quantities increase, so does the local density along with a concurrent rise in the maximum pressure. Intriguingly, the model demonstrates the lowest pressure at Z = 35 Å accompanied by the emergence of a small crescent-shaped region with a reduced density. Throughout the pressure ascension phase, the rate of the maximum pressure change escalates with an increase in the number of bubbles. Conversely, during the pressure descent phase, the rate of the maximum pressure change diminishes with a growing number of bubbles. However, it is important to note that the maximum pressure does not exhibit a direct correlation with the number of bubbles. Ultimately, this study provides valuable technical guidance and a theoretical foundation for the integration of ultrasonic cavitation in industrial production processes.

Comparing Sonazoid contrast-enhanced ultrasound to contrast-enhanced CT and MRI for differentially diagnosing renal lesions: a prospective multicenter study.

PURPOSE: To evaluate the diagnostic performance of contrast-enhanced (CE) ultrasound using Sonazoid (SNZ-CEUS) by comparing with contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) for differentiating benign and malignant renal masses. MATERIALS AND METHODS: 306 consecutive patients (from 7 centers) with renal masses (40 benign tumors, 266 malignant tumors) diagnosed by both SNZ-CEUS, CE-CT or CE-MRI were enrolled between September 2020 and February 2021. The examinations were performed within 7 days, but the sequence was not fixed. Histologic results were available for 301 of 306 (98.37%) lesions and 5 lesions were considered benign after at least 2 year follow-up without change in size and image characteristics. The diagnostic performances were evaluated by sensitivity, specificity, positive predictive value, negative predictive value, and compared by McNemar's test. RESULTS: In the head-to-head comparison, SNZ-CEUS and CE-MRI had comparable sensitivity (95.60 vs. 94.51%, P = 0.997), specificity (65.22 vs. 73.91%, P = 0.752), positive predictive value (91.58 vs. 93.48%) and negative predictive value (78.95 vs. 77.27%); SNZ-CEUS and CE-CT showed similar sensitivity (97.31 vs. 96.24%, P = 0.724); however, SNZ-CEUS had relatively lower than specificity than CE-CT (59.09 vs. 68.18%, P = 0.683). For nodules > 4 cm, CE-MRI demonstrated higher specificity than SNZ-CEUS (90.91 vs. 72.73%, P = 0.617) without compromise the sensitivity. CONCLUSIONS: SNZ-CEUS, CE-CT, and CE-MRI demonstrate desirable and comparable sensitivity for the differentiation of renal mass. However, the specificity of all three imaging modalities is not satisfactory. SNZ-CEUS may be a suitable alternative modality for patients with renal dysfunction and those allergic to gadolinium or iodine-based agents.

Efficacy, safety, and survival findings after long-term follow-up of ZGJAK002: A phase 2 study comparing jaktinib at 100 mg twice daily (BID) and 200 mg once daily (QD) in patients with myelofibrosis.

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.

Construction of Cobalt-Containing Polyoxovanadate-Based Inorganic-Organic Hybrids as Heterogeneous Catalysts for the Selective Oxidation of Sulfides.

In order to develop efficient catalysts for the selective oxidation of sulfides, in this work, two polyoxovanadate-based inorganic-organic hybrids, [Co(H2O)3(3-bpfb)0.5(V2O6)]·(3-bpfb)0.5 (1) and [Co(H2O)2(4-bpfb)0.5(V2O6)] (2) [3-bpfb = N, N'-bis(3-pyridylformamide)-1, 4-benzenediamine, 4-bpfb = N, N'-bis(4-pyridylformamide)-1, 4-benzenediamine], were isolated under hydrothermal conditions. The structures of 1 and 2 embodied two kinds of different cobalt-containing polyoxovanadate-based inorganic chains. Compound 1 contained a one-dimensional inorganic zigzag chain created by the aggregation of {V2O6} clusters with each other, on which Co (II) ions were fixed. But it was an inorganic dimeric chain constructed from two linear {V2O6} cluster-based chains gathered by Co (II) ions in 2. The 3-bpfb and 4-bpfb ligands, as the bidentate linkers, coordinated with two Co (II) ions from adjacent chains to organize them into two-dimensional layers. The hydrogen bonds made important contributions to the formation of supramolecular structures of the two compounds. The two compounds served as heterogeneous catalysts and exhibited efficient activity for the selective oxidation of sulfide to sulfoxide and could be reused at least six times without loss of catalytic activity and stability.

Four POM-Viologen Color-Changing Materials with Fast Color Response under Various External Stimuli.

Four kinds of polyoxometalate (POM)-viologen compounds were synthesized by hydrothermal method, namely (1-cby)2·[H2(SiMo12O40)]·2H2O (1), (1-cby)2·[H2(SiW12O40)]·2H2O (2), (1-cby)2·(1,1'-bcby)2·{H4[Co4(H2O)2(PW9O34)2]}·12H2O (3), (1-cby)·(1,1'-bcby)·[H(α-PW11O39)CoII(1-cby)]·8H2O (4) (1-cby·Br = 1-Cyclopropylmethyl-[4,4']bipyridinyl-1-ium bromide, 1,1'-bcby·Br = 1,1'-Bis-cyclopropylmethyl-[4,4']bipyridinyl-1-ium bromide). These four POM-viologen compounds exhibit one-dimensional supramolecular network structures. Especially, compound 3 contains a rare sandwich POM subunit {Co4(H2O)2(PW9O34)2}10-. These four compounds can be used as color-changing materials, and they all exhibit noticeable color changes upon exposure to light, heat, and electricity. The discoloration mechanism involves viologen derivatives with electron-deficient properties accepting electrons from POM with electron-rich properties under external stimulation, leading to the formation of viologen free radicals. Among them, compounds 1 and 2 also have good properties for ink-free erasable printing, double anticounterfeiting, and ultraviolet detector because of their rapid color response to ultraviolet (UV) light. In addition, compounds 1-4 also show different color changes in the detection of volatile amines.

Tailoring the Coordination Microenvironment of Polymolybdate within a Metal-Organic Coordination System for Enhanced Capacitive Activity.

The design of a low-cost and efficient electrode material is crucial for electrochemical energy storage. Effectual utilization of polymolybdate as an electrode material for a supercapacitor is promising. Meanwhile, the coordination microenvironments of polymolybdate sho potential effects on its performance. Herein, we designed and synthesized four polymolybdate-based metal-organic complexes using a structure design strategy. Their structures were characterized and analyzed using single crystallographic data. The theoretical calculations revealed that the coordination microenvironments of polymolybdate play a vital role in the hydrogen ions migration. High H adsorption capacity can obviously boost the electrochemical activity. The 1-based glassy carbon electrode showed the highest specific capacitance value of 1739.4 F·g-1 at the current density of 1 A·g-1. Meanwhile, the carbon cloth-based electrode fabricated by complex 1 (1/CC) also displayed a high capacitance performance. A hybrid supercapacitor was assembled using the 1/CC electrodes and showed a high energy density of 29.0 Wh kg-1 at the power density of 0.80 kW kg-1.

Two {CuI[P4Mo6]2}-Based Coordination Polymers Incorporating In Situ Converted Tetrapyridyl Ligands for Trace Analysis of Nitrofuran Antibiotics.

Nitrofurans are important synthetic broad-spectrum antibacterial drugs with the basic structure of 5-nitrofuran. Due to their toxicity, it is essential to develop a sensitive sensor with strong anti-interference capabilities for their detection. In this work, two {P4Mo6O31}12--based compounds, [H4(HPTTP)]2{CuI[Mo12O24(OH)6(PO4)3(HPO4)(H2PO4)4]}·xH2O (x = 13 for (1), 7 for (2); HPTTP = 4,4',4″,4‴-(1H-pyrrole-2,3,4,5-tetrayl)tetrapyridine), exhibiting similar coordination but distinct stacking modes. Both compounds were synthesized and used for the electrochemical detection of nitrofuran antibiotics. The tetrapyridine-based ligand was generated in situ during assembly, and its potential mechanism was discussed. Composite electrode materials, formed by mixing graphite powder with compounds 1-2 and physically grinding them, proved to be highly effective in the electrochemical trace detection of furazolidone (FZD) and furaltadone hydrochloride (FTD·HCl) under optimal conditions. Besides, the possible electrochemical detection mechanisms of two nitro-antibiotics were studied.

Neoadjuvant Photodynamic Therapy: An Updated Therapeutic Approach for Non-Melanoma Skin Cancers.

OPINION STATEMENT: Non-melanoma skin cancers (NMSCs) are the most common malignancy and surgical excision is considered treatment of choice for the majority of cases. However, surgery can be very extensive in cases of large, multiple, or cosmetic-sensitive tumors located on areas such as scalp and face or genital region, leading to significant functional and cosmetic deficit. Aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a widely used approach in a variety of skin diseases, demonstrating remarkable efficacy in treatment of actinic keratosis, Bowen disease and basal cell carcinoma. Besides, when employed as a preoperative intervention, ALA-PDT effectively reduces tumor size and minimizes subsequent local surgical morbidity. With its minimally invasive nature and proven effectiveness, ALA-PDT holds significant promise as a neoadjuvant treatment option for NMSCs. In cases where the tumor is large, invasive, multiple, or located in cosmetically and functionally sensitive areas, or when considering patient factors such as age, comorbidity, willingness to undergo surgery, and post-operative quality-of-life, surgical intervention or radiotherapy alone may be impracticable or unacceptable. In such scenarios, neoadjuvant ALA-PDT can offer remarkable outcomes. In order to further ensure the maximum benefit of patients from neoadjuvant PDT, collaboration with multidisciplinary teams and whole-process management may be in need.

Real-world data of 5-aminolaevulinic acid-mediated photodynamic therapy for Bowen disease: a 10-year retrospective study in patients with darker-coloured skin (2011-2021).

BACKGROUND: Photodynamic therapy (PDT) has been strongly recommended as an excellent alternative treatment for Bowen disease (BD). However, reported data on 5-aminolaevulinic acid-mediated PDT (ALA-PDT) with red-light irradiation are limited and the long-term effectiveness remains to be determined, especially in dark-skinned populations. OBJECTIVES: We aimed to review routine clinical practice in the field of BD treatment with ALA-PDT over an extended study period (2011-2021), calculate the overall clearance rate, and explore and evaluate factors that might affect the effectiveness of therapy in a real-world setting. METHODS: The medical records of patients with BD who received ALA-PDT with red-light irradiation between February 2011 and June 2021 were reviewed and summarized. Univariate and multivariate analyses of clinically relevant variables that may affect treatment outcomes were conducted to identify risk predictors. RESULTS: The overall clearance rate of 122 BD lesions was 89.3% with a median follow-up time of 36 months. The correlation between the effectiveness and fluorescence intensity of pre-PDT or PDT sessions was statistically significant after eliminating the interference of confounding factors. All recurrences occurred in the first 2 years following ALA-PDT. CONCLUSIONS: ALA-PDT is an effective treatment for BD in patients with darker-coloured skin. Well-executed operations and effective pretreatment are the determinants of effectiveness. Fluorescence intensity of pre-PDT appeared to be a significant predictor of final effectiveness. In addition, 2 years of follow-up is necessary following ALA-PDT.

Revealing spatiotemporal inequalities, hotspots, and determinants in healthcare resource distribution: insights from hospital beds panel data in 2308 Chinese counties.

BACKGROUND: Ensuring universal health coverage and equitable access to health services requires a comprehensive understanding of spatiotemporal heterogeneity in healthcare resources, especially in small areas. The absence of a structured spatiotemporal evaluation framework in existing studies inspired us to propose a conceptual framework encompassing three perspectives: spatiotemporal inequalities, hotspots, and determinants. METHODS: To demonstrate our three-perspective conceptual framework, we employed three state-of-the-art methods and analyzed 10 years' worth of Chinese county-level hospital bed data. First, we depicted spatial inequalities of hospital beds within provinces and their temporal inequalities through the spatial Gini coefficient. Next, we identified different types of spatiotemporal hotspots and coldspots at the county level using the emerging hot spot analysis (Getis-Ord Gi* statistics). Finally, we explored the spatiotemporally heterogeneous impacts of socioeconomic and environmental factors on hospital beds using the Bayesian spatiotemporally varying coefficients (STVC) model and quantified factors' spatiotemporal explainable percentages with the spatiotemporal variance partitioning index (STVPI). RESULTS: Spatial inequalities map revealed significant disparities in hospital beds, with gradual improvements observed in 21 provinces over time. Seven types of hot and cold spots among 24.78% counties highlighted the persistent presence of the regional Matthew effect in both high- and low-level hospital bed counties. Socioeconomic factors contributed 36.85% (95% credible intervals [CIs]: 31.84-42.50%) of county-level hospital beds, while environmental factors accounted for 59.12% (53.80-63.83%). Factors' space-scale variation explained 75.71% (68.94-81.55%), whereas time-scale variation contributed 20.25% (14.14-27.36%). Additionally, six factors (GDP, first industrial output, local general budget revenue, road, river, and slope) were identified as the spatiotemporal determinants, collectively explaining over 84% of the variations. CONCLUSIONS: Three-perspective framework enables global policymakers and stakeholders to identify health services disparities at the micro-level, pinpoint regions needing targeted interventions, and create differentiated strategies aligned with their unique spatiotemporal determinants, significantly aiding in achieving sustainable healthcare development.

PM2.5 chemical components are associated with in-hospital case fatality among acute myocardial infarction patients in China.

Recent studies have linked the cardiovascular events with the exposure to ambient fine particulate matter (PM2.5); however, the impact of PM2.5 chemical components on acute myocardial infarction (AMI) case fatality remains poorly understood. To address this gap, we included 178,340 hospitalised patients with AMI utilising the inpatient discharge database from Sichuan, Shanxi, Guangxi, and Guangdong, China spanning 2014-2019. We evaluated exposure to PM2.5 and its components (black carbon (BC), organic matter (OM), sulphate (SO42-), nitrate (NO3-), and ammonium (NH4+)) using bilinear interpolation based on the patient's residential address. We used mixed-effects logistic regression models to investigate the associations of PM2.5 and its five components with in-hospital AMI case fatality. Per interquartile range (IQR) increment in short-term exposure (7-day average) to overall PM2.5 (odds ratio (OR): 1.086, 95 % confidence interval (CI): 1.045-1.128), SO42-(1.063, 1.024-1.104), BC (1.055, 1.023-1.089), OM (1.052, 1.019-1.086, and NO3- (1.045, 1.003-1.089) were significantly associated with high risk of in-hospital AMI case fatality. The ORs per IQR increment in long-term exposure (annual average) were 1.323 (95 % CI: 1.255-1.394) for PM2.5, followed by BC (1.271, 1.210-1.335), OM (1.243, 1.188-1.300), SO42- (1.212, 1.157-1.270), NO3- (1.116, 1.075-1.159), and NH4+ (1.068, 1.031-1.106). Our study suggests that PM2.5 chemical components might be important risk factors for in-hospital AMI case fatality, highlighting the importance of targeted reduction of PM2.5 emissions, particularly BC, OM, and SO42-.

Krüppel-like factor 4 modulates the miR-101/COL10A1 axis to inhibit renal fibrosis after AKI by regulating epithelial-mesenchymal transition.

Acute kidney injury (AKI) can progress to renal fibrosis and chronic kidney disease (CKD), which reduces quality of life and increases the economic burden on patients. However, the molecular mechanisms underlying renal fibrosis following AKI remain unclear. This study tested the hypothesis that the Krüppel-like factor 4 (KLF4)/miR-101/Collagen alpha-1X (COL10A1) axis could inhibit epithelial-mesenchymal transition (EMT) and renal fibrosis after AKI in a mouse model of ischemia-reperfusion (I/R)-induced renal fibrosis and HK-2 cells by gene silencing, overexpression, immunofluorescence, immunohistochemistry, real-time quantitative PCR, Western blotting, dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) and ELISA. Compared with the Sham group, I/R induced renal tubular and glomerular injury and fibrosis, and increased the levels of BUN, serum Scr and neutrophil gelatinase-associated lipocalin (NGAL), Col10a1 and Vimentin expression, but decreased E-cadherin expression in the kidney tissues of mice at 42 days post-I/R. Similarly, hypoxia promoted fibroblastic morphological changes in HK-2 cells and enhanced NGAL, COL10A1, Vimentin, and α-SMA expression, but reduced E-cadherin expression in HK-2 cells. These pathological changes were significantly mitigated in COL10A1-silenced renal tissues and HK-2 cells. KLF4 induces miR-101 transcription. More importantly, hypoxia upregulated Vimentin and COL10A1 expression, but decreased miR-101, KLF4, and E-cadherin expression in HK-2 cells. These hypoxic effects were significantly mitigated or abrogated by KLF4 over-expression in the HK-2 cells. Our data indicate that KLF4 up-regulates miR-101 expression, leading to the downregulation of COL10A1 expression, inhibition of EMT and renal fibrosis during the pathogenic process of I/R-related renal fibrosis.